Phenotypic anchoring of gene expression changes during estrogen-induced uterine growth.

A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17 beta-estradiol (E2).

The effects of the phytoestrogen genistein on the postnatal development of the rat.

The present studies report the effects on neonatal rats of oral exposure to genistein during the period from birth to postnatal day (PND) 21 to generate data for use in assessing human risk following oral ingestion of genistein. Failure to demonstrate significant exposure of the newborn pups via the mothers milk led us to subcutaneously inject genistein into the pups over the period PND 1-7, followed by daily gavage dosing to PND 21. The targeted doses throughout were 4 mg/kg/day genistein (equivalent to the average exposure of infants to total isoflavones in soy milk) and a dose 10 times higher than this (40 mg/kg genistein).

Responses in the respiratory tract of rats following exposure to sulphuric acid aerosols for 5 or 28 days.

Sulphuric acid mists have been classified by the International Agency for Research on Cancer as being carcinogenic to humans based on epidemiological findings of respiratory tract tumours. To determine if early changes in the respiratory tract following exposure to sulphuric acid (H(2)SO(4)) aerosols are consistent with the possible development of tumours after extended periods of exposure, groups of female rats were exposed to respirable aerosols of H(2)SO(4) at target concentrations of 0, 0.2, 1.

Pulmonary responses and recovery following single and repeated inhalation exposure of rats to polymeric methylene diphenyl diisocyanate aerosols.

Acute and repeated inhalation exposures (for 28 days) to polymeric methylene diphenyl diisocyanate (PMDI) were performed in rats. Investigations were made at the end of exposures and after 3, 10 and 30 days of recovery following single acute exposures and after 30 days of recovery following 28 days of exposure. Acute exposures to 10, 30 or 100 mg m(-3) PMDI produced clinical signs in all animals that were consistent with exposure to irritant aerosols.

Downregulation of lactoferrin by PPARalpha ligands: role in perturbation of hepatocyte proliferation and apoptosis.

PPARalpha (peroxisome proliferator activated receptor alpha) is a transcription factor that mediates the rodent liver tumorigenic responses to peroxisome proliferators via regulation of genes that remain to be identified. Using microarray gene expression profiling of mRNA from wild type versus PPARalpha null mice, we detected a 3- to 7-fold downregulation of hepatic lactoferrin (LF) in response to the PP, diethylhexylphthalate (DEHP; 1150 mg/kg). Northern blot analyses confirmed a significant downregulation of LF mRNA by DEHP in wild type mouse liver.

Prediction of rodent nongenotoxic carcinogenesis: evaluation of biochemical and tissue changes in rodents following exposure to nine nongenotoxic NTP carcinogens.

We studied nine presumed nongenotoxic rodent carcinogens, as defined by the U.S. National Toxicology Program (NTP), to determine their ability to induce acute or subacute biochemical and tissue changes that may act as useful predictors of nongenotoxic rodent carcinogenesis.